CS267331B1 - Method of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines preparation - Google Patents
Method of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines preparation Download PDFInfo
- Publication number
- CS267331B1 CS267331B1 CS88345A CS34588A CS267331B1 CS 267331 B1 CS267331 B1 CS 267331B1 CS 88345 A CS88345 A CS 88345A CS 34588 A CS34588 A CS 34588A CS 267331 B1 CS267331 B1 CS 267331B1
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- CS
- Czechoslovakia
- Prior art keywords
- methyl
- oxohexyl
- formula
- alkylxanthines
- preparation
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 10
- 239000003513 alkali Substances 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229940035893 uracil Drugs 0.000 claims description 4
- -1 5-oxohexyl Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- PFCHFHIRKBAQGU-UHFFFAOYSA-N 3-hexanone Chemical compound CCCC(=O)CC PFCHFHIRKBAQGU-UHFFFAOYSA-N 0.000 claims 1
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 abstract description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 abstract 1
- BBTNLADSUVOPPN-UHFFFAOYSA-N 5,6-diaminouracil Chemical compound NC=1NC(=O)NC(=O)C=1N BBTNLADSUVOPPN-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- AHSKYWGYRVWJLX-UHFFFAOYSA-N 3-methyl-7-(2-methylpropyl)-1-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CC(C)C AHSKYWGYRVWJLX-UHFFFAOYSA-N 0.000 description 2
- CMDIDTNMHQUVPE-UHFFFAOYSA-N 6-chlorohexan-2-one Chemical compound CC(=O)CCCCCl CMDIDTNMHQUVPE-UHFFFAOYSA-N 0.000 description 2
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 2
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- CZGOECYPTLSLNI-UHFFFAOYSA-N 6-bromohexan-2-one Chemical compound CC(=O)CCCCBr CZGOECYPTLSLNI-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Riešenie sa týká jednostupňovej přípravy farmakologicky účinných l-/5-oxohe-· xyl/-3-metyl-7-alkylxantínov z l-metyl-5- -/N-formyl-N-alkyl/-amino-6-aminouraciIov a 6-halogen-hexanónov pósobenia alkalických uhličitanov v prostředí aprotického polárného rozpúšťadla při teplote 60 C až 180 °C.The solution relates to single stage preparation pharmacologically active l- / 5-oxohe- xyl / 3-methyl-7-alkylxanthines from 1-methyl-5- - [N-formyl-N-alkyl] -amino-6-aminouration and 6-halo-hexanones act by alkali carbonates in an aprotic environment polar solvent at 60 ° C to 50 ° C 180 ° C.
Description
Predmetom vynálezu je spOsob přípravy l-/5-oxohexyl/-3-metyl-7-alkylxantínov všeobecné ho vzorca IThe present invention relates to a process for the preparation of 1- (5-oxohexyl) -3-methyl-7-alkylxanthines of the general formula I
/1/ kde R je lineárny alebo rozvětvený alkyl 0χ až C4< Látky vzorca I sa vyznačujú farmakologickým účinkom na srdovocievny systém.(1) wherein R is a linear or branched alkyl 0 χ to C 4 <The compounds of formula I are characterized by a pharmacological effect on the cardiovascular system.
Příprava předmětných, zlúčenín vzorca I je opísaná dvorná základnými spůsobmi:The preparation of the present compounds of formula I is described in the following basic ways:
1. alkyláclou 3-metyl-7-alkylxantínov s 6-halogen-2-hexanónmi, ako uvádza napr. ČS AO1. alkylation of 3-methyl-7-alkylxanthines with 6-halogen-2-hexanones, as indicated for example by ČS AO
č. 237719, DOS 2330 742.No. 237719, DOS 2330 742.
2. cyklizáciou l-metyl-3-/5-oxohexyl/-5-alkyl-amino-6-aminouracilov /Jap. pat. 147091/.2. by cyclization of 1-methyl-3- (5-oxohexyl) -5-alkylamino-6-aminouracils [Jap. pat. 147091 /.
Podstata postupu podlá vynálezu sa vyznačuje· tým, že ea nechá reagovat l-metyl-5-/N-alkyl-N-formyl/smino-ó-aminouracil všeobecného vzorca IIThe process according to the invention is characterized in that ea is reacted with 1-methyl-5- (N-alkyl-N-formyl) amino-6-aminouracil of the general formula II
II /11/ kde R představuje lineárny alebo rozvětvený alkyl až C^, s 6-halcgenhexanonom všeobecného vzorca III.II / 11 / wherein R represents linear or branched alkyl to C 1-6, with 6-halohexanone of general formula III.
ch3-co-ch2-ch2-ch2-ch2-x /111/ kde X je atom chlóru alebo brómu, za přítomnosti uhličitanov alkalických kovov, s výhodou uhličitanu draselného v prostředí aprotického polárného rozpúšíadla, s výhodou dimetylformamidu, při zvýšenej teplota 60 °C až 180 °C.ch 3 -co-ch 2 -ch 2 -ch 2 -ch 2 -x (111) wherein X is a chlorine or bromine atom, in the presence of alkali metal carbonates, preferably potassium carbonate in an aprotic polar solvent, preferably dimethylformamide, at elevated temperature 60 ° C to 180 ° C.
V jednom reakčnom stupni dochádza jednak k alkylácii 6-halogénhexenonom vzorca III a jednak k cyklizáoii za vzniku xantínového skeletu. V reakoii ea používá poměr molárnych dielov 6-halogénhexanónu vzorca III ku uracilu vzorca ·ΙΙ 0,8 s 1 až 1,2 s 1 a poměr molárnych dielov alkalického uhličitanu ku uracilu 2 : 0,8 až 4 : 1.In one reaction step, alkylation occurs with a 6-halohexenone of formula III and cyclization to form a xanthine backbone. In reaction ea, it uses a molar ratio of 6-halohexanone of formula III to uracil of formula · ΙΙ 0.8 s 1 to 1.2 s 1 and a molar ratio of alkali carbonate to uracil of 2: 0.8 to 4: 1.
Výhodou postupu podlá vynálezu je skrátenie reakčných stupňov syntézy, nakolko nie je nutné připravit 3-metyl-7-alkylxantín. V óalšom je postup objasněný v príkladoch bez toho, že by sa na tieto výlučné obmedzoval.The advantage of the process according to the invention is the shortening of the reaction steps of the synthesis, since it is not necessary to prepare 3-methyl-7-alkylxanthine. In the following, the procedure is illustrated in the examples without being limited to these only.
Příklad 1 · l-/5-oxohexyl/-3-metyl-7-propylxantínExample 1 · 1- (5-oxohexyl) -3-methyl-7-propylxanthine
Zmes 22,3 g l-metyl-5-j/”/N-formyl-N-/-propyl/_7 amino-6-aminouracilu a 28 g uhličitanu draselného sa zahřeje v 100 ml dimetylformamitu na teplo 140 °C. Následná sa přidá v priebehu 1 hodiny 14,4 g 6-chlóro-2-hexanónu. Řeakčná zmes sa mieša ešte 6 hodin. Po oddělení sa odfiltruje a zahustí sa vákuovo. Získá sa 26 g, t.j. 86 % l-/5-oxo-hexyl/-3-metyl-7-n-propylxantínu s t.t, 62 °C až 64 °C, krystalizované s terč, butylmetyléteru,A mixture of 22.3 g of 1-methyl-5-N-formyl-N - [- propyl] -7-amino-6-aminouracil and 28 g of potassium carbonate is heated in 100 ml of dimethylformamide to a heat of 140 ° C. 14.4 g of 6-chloro-2-hexanone are then added over the course of 1 hour. The reaction mixture was stirred for another 6 hours. After separation, it is filtered off and concentrated in vacuo. 26 g, i.e. 86% of 1- (5-oxo-hexyl) -3-methyl-7-n-propylxanthine with a melting point of 62 DEG-64 DEG C., crystallized from tert-butyl methyl ether, are obtained.
Příklad 2 l-/5-oxohexyl/-3,7-dimetylxantínExample 2 1- (5-Oxohexyl) -3,7-dimethylxanthine
Postupom apologickým ako v příklade 1 sa spracuje 19,6 g l-mstyl-5-/N-metyl-N-íormyl/ amino-6-aminouracilu a 20 g 6-bróm-2-hexanónu při teplote 120 °C. Získá sa 20 g, t.j. 70 % l-/5-oxohexyl/-3,7-dimetylxantínu.19.6 g of 1-methyl-5- (N-methyl-N-formyl) amino-6-aminouracil and 20 g of 6-bromo-2-hexanone are treated at 120 DEG C. according to the procedure apologically to Example 1. 20 g, i.e. 70% of 1- (5-oxohexyl) -3,7-dimethylxanthine are obtained.
OS 267331 BlOS 267331 Bl
Příklad 3 l-/5-oxohexyl/-3-metyl-7-isobutylxantínExample 3 1- (5-Oxohexyl) -3-methyl-7-isobutylxanthine
Postupem anologickým ako ,v příklade 1 sa spracuje 20,1 g 1-metyl-5-/N-isobuty1-N-formyl/amino-6-aminouracilu a 16,3 g 6-chloro-2-hexanónu získá sa 28,2 g, t.j. 90 % l-/5-oxohexyl/-3-mety1-7-isobutyIxant ínu.Following an analogous procedure to Example 1, 20.1 g of 1-methyl-5- (N-isobutyl-N-formyl) amino-6-aminouracil and 16.3 g of 6-chloro-2-hexanone were treated to give 28.2 g. g, i.e. 90% of 1- (5-oxohexyl) -3-methyl-7-isobutylxanthine.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS88345A CS267331B1 (en) | 1988-01-19 | 1988-01-19 | Method of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS88345A CS267331B1 (en) | 1988-01-19 | 1988-01-19 | Method of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS34588A1 CS34588A1 (en) | 1989-06-13 |
| CS267331B1 true CS267331B1 (en) | 1990-02-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS88345A CS267331B1 (en) | 1988-01-19 | 1988-01-19 | Method of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS267331B1 (en) |
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1988
- 1988-01-19 CS CS88345A patent/CS267331B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS34588A1 (en) | 1989-06-13 |
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